Die Bedeutung der Mikrozirkulation bei der Absto�ung frei transplantierter Langerhans Inseln

Menger,; Wolf, Beate; Höbel, R; Hu, Schorlemmer; Meßmer, K.

doi:10.1007/bf00186815

Cited by 23 publications

(2 citation statements)

References 20 publications

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“…However, immune responses do not seem to affect the revascularization process as observed during the first week [145]. However, immune responses do not seem to affect the revascularization process as observed during the first week [145].…”

Section: Islet Graft Vasculaturementioning

confidence: 87%

Physiology of Islet Engraftment

Kampf

Carlsson

2006

IEMAMC

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Pancreatic islet transplantation is a tempting strategy to treat patients with type 1 diabetes mellitus, since if successful it could provide a cure for the disease. At present, there is, however, a poor long-term outcome of such transplantations compared to the results for whole pancreas transplantation. One explanation for this may be inadequate engraftment of the transplanted cells in the new microenvironment. The engraftment process includes immediate survival in the post transplantation phase. There is likely extensive cell death immediately following transplantation mainly due to inflammatory responses triggered by e.g. hypoxia. Also the long-term survival and function of the transplanted islets is encompassed by the term engraftment. This is influenced by the cellular turn-over rate, and the degree of revascularization and reinnervation of the islet tissue. To regain optimal function in surviving cells, new vascular and nervous systems similar to those in endogenous islets need to form. Both qualitative and quantitative changes compared to endogenous islets have, however, been described in the new vascular system that develops following transplantation, and these changes seem to have consequences for islet blood perfusion, metabolism and function. Comparatively little is known regarding the extent of functional re-growth of nerves that occurs, and its influence on graft function. This review also discusses the challenges of engraftment that seem specific for intraportally transplanted islets, e.g. the instant blood mediated immune reaction, the loss of glucagon response to hypoglycemia, and the lower β-cell proliferation rate in intraportally transplanted islets than in islets grafted to the kidney.

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Section: Islet Graft Vasculaturementioning

confidence: 87%

Physiology of Islet Engraftment

Kampf

Carlsson

2006

IEMAMC

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“…There is still much to learn about the optimization of Tol-DC therapy for clinical islet transplantation, such as what dose, frequency, and route of administration to use, and the length of time appropriate for treating with Tol-DC. Even so, small animal models provide important insights into the mechanisms underlying tolerance induction [1], [29], [30]. We believe that Tol-DCs will one-day play a critical role in the treatment of clinical islet transplantation for T1D.…”

Section: Discussionmentioning

confidence: 99%

Adoptive Infusion of Tolerogenic Dendritic Cells Prolongs the Survival of Pancreatic Islet Allografts: A Systematic Review of 13 Mouse and Rat Studies

Sun

Shan

et al. 2012

PLoS ONE

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ObjectiveThe first Phase I study of autologous tolerogenic dendritic cells (Tol-DCs) in Type 1 diabetes (T1D) patients was recently completed. Pancreatic islet transplantation is an effective therapy for T1D, and infusion of Tol-DCs can control diabetes development while promoting graft survival. In this study, we aim to systematically review islet allograft survival following infusion of Tol-DCs induced by different methods, to better understand the mechanisms that mediate this process.MethodsWe searched PubMed and Embase (from inception to February 29th, 2012) for relevant publications. Data were extracted and quality was assessed by two independent reviewers. We semiquantitatively analyzed the effects of Tol-DCs on islet allograft survival using mixed leukocyte reaction, Th1/Th2 differentiation, Treg induction, and cytotoxic T lymphocyte activity as mechanisms related-outcomes. We discussed the results with respect to possible mechanisms that promote survival.ResultsThirteen articles were included. The effects of Tol-DCs induced by five methods on allograft survival were different. Survival by each method was prolonged as follows: allopeptide-pulsed Tol-DCs (42.14±44 days), drug intervention (39 days), mesenchymal stem cell induction (23 days), genetic modification (8.99±4.75 days), and other derivation (2.61±6.98 days). The results indicate that Tol-DC dose and injection influenced graft survival. Single-dose injections of 104 Tol-DCs were the most effective for allograft survival, and multiple injections were not superior. Tol-DCs were also synergistic with immunosuppressive drugs or costimulation inhibitors. Possible mechanisms include donor specific T cell hyporesponsiveness, Th2 differentiation, Treg induction, cytotoxicity against allograft reduction, and chimerism induction.ConclusionsTol-DCs induced by five methods prolong MHC mismatched islet allograft survival to different degrees, but allopeptide-pulsed host DCs perform the best. Immunosuppressive or costimulatory blockade are synergistic with Tol-DC on graft survival. Multiple injections are not superior to single injection. Yet more rigorously designed studies with larger sample sizes are still needed in future.

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The quinoline-3-carboxamide Linomide inhibits angiogenesis in vivo

Borgström¹,

Filho²,

Vajkoczy³

et al. 1994

Cancer Chemother. Pharmacol.

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Linomide (Roquinimex) has antitumor activity when given in vivo (but not when applied in vitro) that has been attributed to immune host mechanisms. Recent studies, however, suggest that Linomide may also possess antiangiogenic properties. The aim of the present study was to evaluate the antiangiogenic effect of Linomide using an intravital microscopic technique. Syngeneic pancreatic islets were isolated and implanted into the dorsal skinfold chamber of Syrian golden hamsters. This model allows detailed repeated in vivo observations and quantitative analysis of revascularization of pancreatic islet grafts. The neovascularization process of the islets is a highly reproducible phenomenon that is completed within about 2 weeks, resulting in a microvascular network very similar to that of islets in situ. The plasma concentration profile of Linomide following a single oral dose of the compound was determined. The elimination of Linomide was fast, the half-life being 2.6 +/- 0.2 h. Due to the short half-life, the hamsters were given Linomide twice a day. One group of animals (n = 9) was force-fed Linomide (100 mg/kg per day) from the day of implantation throughout the 2-week observation period, and the results were compared with those obtained in a nontreated control group (n = 7). At days 6, 10, and 14 after implantation, the neo-vasculature of the islets was examined. In the control group, 91% +/- 4% (mean +/- SEM) of the islets showed the first signs of angiogenesis at day 6, whereas in the Linomide-treated group the corresponding value was 48% +/- 12%. At days 10 and 14, the "take-rate" in the control group increased to 94% +/- 3% for day 0 and to 94% +/- 4% (n = 6) for day 14, whereas in the treated group the corresponding take-rate was 67% +/- 11% and 72% +/- 12%, respectively. The functional capillary density in the control group at days 6, 10, and 14 was 223 +/- 17,348 +/- 29, and 495 +/- 29 cm-1, respectively, and that in the Linomide treated group was 91 +/- 28, 181 +/- 43, and 229 +/- 47 cm-1, respectively. These results demonstrate that Linomide suppresses the neovascularization of the islet grafts by both delaying the onset of and reducing the percentage of islets displaying angiogenesis as well as by decreasing the rate of proliferation of capillary endothelium of the revascularized islets.

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Die Bedeutung der Mikrozirkulation bei der Absto�ung frei transplantierter Langerhans Inseln

Cited by 23 publications

References 20 publications

Physiology of Islet Engraftment

Physiology of Islet Engraftment

Adoptive Infusion of Tolerogenic Dendritic Cells Prolongs the Survival of Pancreatic Islet Allografts: A Systematic Review of 13 Mouse and Rat Studies

The quinoline-3-carboxamide Linomide inhibits angiogenesis in vivo

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